1,4-benzodiazepines with 5- and 6-membered heterocyclic rings, useful as gastrointestinal and CNS agents

ABSTRACT

Aromatic 1,4-benxodiazepines with fused 5- or 6-membered heterocyclic rings which are antagonists of cholecystokinins and/or gastrin, and are useful in the treatment or prevention of CCK-related and/or gastrin-related disorders of the gastrointestinal, central nervous and appetite regulatory systems; compositions comprising these compounds; and methods of treatment employing these compounds.

BACKGROUND OF THE INVENTION

Cholecystokinins (CCK) and gastrin are structurally-relatedneuropeptides which exist in gastrointestinal tissue and in the thecentral nervous system (see, V. Mutt, Gastrointestinal Hormones, G. B.J. Glass, Ed., Raven Press, N.Y., p. 169 and G. Nisson, ibid, p. 127).

Cholecystokinins include CCK-33, a neuropeptide of thirty-three aminoacids in its originally isolated form (see, Mutt and Jorpes, Biochem. J.125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (anaturally-ocurring neuropeptide, also, and the minimum fully activesequence), and 39- and 12-amino acid forms, while gastrin occurs in 34-,17- and 14-amino acid forms, with the minimum active sequence being theC-terminal pentapeptide, Gly-Trp-Met-Asp-Phe-NH₂, which is the commonstructural element shared by both CCK and gastrin.

CCK's are believed to be physiological satiety hormones, therebypossibly playing an important role in appetite regulation (G. P. Smith,Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, RavenPress, New York, 1984, p. 67), as well as also stimulating colonicmotility, gall bladder contraction, pancreatic enzyme secretion, andinhibiting gastric emptying. They reportedly co-exist with dopamine incertain mid-brain neurons and thus may also play a role in thefunctioning of dopaminergic systems in the brain, in addition to servingas neurotransmitters in their own right (see: A. J. Prange et al.,"Peptides in the Central Nervous System", Ann. Repts. Med. Chem. 17, 31,33 [1982] and references cited therein; J. A. Williams, Biomed. Res. 3107 [1982]); and J. E. Morley, Life Sci. 30, 479, [1982]).

The primary role of gastrin, on the other hand, appears to bestimulation of the secretion of water and electrolytes from the stomach,and, as such, it is involved in control of gastric acid and pepsinsecretion. Other physiological effects of gastrin then include increasedmucosal blood flow and increased antral motility, with rat studieshaving shown that gastrin has a positive trophic effect on the gastricmucosa, as evidenced by increased DNA, RNA and protein synthesis.

Antagonists to CCK and to gastrin have been useful for preventing andtreating CCK-related and/or gastrin-related disorders of thegastrointestinal (GI) and central nervous (CNS) systems of animals,especially of humans. Just as there is some overlap in the biologicalactivities of CCK and gastrin, antagonists also tend to have affinityfor both receptors. In a practical sense, however, there is enoughselectivity to the different receptors that greater activity againstspecific CCK- or gastrin-related disorders can often also be identified.

Selective CCK antagonists are themselves useful in treating CCK-relateddisorders of the appetite regulatory systems of animals as well as inpotentiating and prolonging opiate-mediated analgesia, thus havingutility in the treatment of pain [see P. L. Faris et al., Science 226,1215 (1984)], while selective gastrin antagonists are useful in themodulation of CNS behavior, as a palliative for gastrointestinalneoplasms, and in the treatment and prevention of gastrin-relateddisorders of the gastrointestinal system in humans and animals, such aspeptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia andother conditions in which reduced gastrin activity is of therapeuticvalue.

Also, since CCK and gastrin also have trophic effects on certain tumors[K. Okyama, Hokkaido J. Med Sci., 60, 206-216 (1985)], antagonists ofCCK and gastrin are useful in treating these tumors [see, R. D.Beauchamp et al., Ann. Surg., 202,303 (1985)].

Four distinct chemical classes of CCK-receptor antagonists have beenreported. The first class comprises derivatives of cyclic nucleotides,of which dibutyryl cyclic GMP has been shown to be the most potent bydetailed structure-function studies (see, N. Barlos et al., Am. J.Physiol., 242, G 161 (1982) and P. Robberecht et al., Mol., Pharmacol.,17, 268 (1980)).

The second class comprises peptide antagonists which are C-terminalfragments and analogs of CCK, of which both shorter(Boc-Met-Asp-Phe-NH₂, Met-Asp-Phe-NH₂), and longer (Cbz-Tyr(SO₃H)-Met-Gly-Trp-Met-Asp-NH₂) C-terminal fragments of CCK can function asCCK antagonists, according to recent structure-function studies (see, R.T. Jensen et al., Biochem. Biophys. Acta., 757, 250 (1983), and M.Spanarkel et al., J. Biol. Chem., 258, 6746 (1983)). The latter compoundwas recently reported to be a partial agonist [see, 8. M. Howard et al.,Gastroenterology 86(5) Part 2, 1118 (1984)].

Then, the third class of CCK-receptor antagonists comprises the aminoacid derivatives: proglumide, a derivative of glutaramic acid, and theN-acyl tryptophans including para-chlorobenzoyl-L-tryptophan(benzotript), [see, W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A.,78, 6304 (1981), R. T. Jensen et al., Biochem. Biophys. Acta., 761, 269(1983)]. All of these compounds, however, are relatively weakantagonists of CCK (IC₅₀ : generally 10⁻⁴ M[although more potent analogsof proglumide have been recently reported in F. Makovec et al.,Arzneim-Forsch Drug Res., 35 (II), 1048 (1985) and in German PatentApplication DE 3522506A1], but down to 10⁻⁶ M in the case of peptides),and the peptide CCK-antagonists have substantial stability andabsorption problems.

In addition, a fourth class consists of improved CCK-antagonistscomprising a nonpeptide of novel structure from fermentation sources [R.S. L. Chang et al., Science, 230, 177-179 (1985)] and 3-substitutedbenzodiazepines based on this structure [published European PatentApplications Nos. 167 919, 167 920 and 169 392, B. E. Evans et al, Proc.Natl. Acad. Sci. U.S.A., 83, p. 4918-4922 (1986) and R. S. L. Chang etal, ibid, p. 4923-4926] have also been reported.

No really effective receptor antagonists of the in vivo effects ofgastrin have been reported (J. S. Morley, Gut Pept. Ulcer Proc.,Hiroshima Symp. 2nd, 1983, p. 1), and very weak in vitro antagonists,such as proglumide and certain peptides have been described [(J.Martinez, J. Med. Chem. 27, 1597 (1984)]. Recently, however,pseudopeptide analogs of tetragastrin have been reported to be moreeffective gastrin antagonists than previous agents [J. Martinez et al.,J. Med. Chem., 28, 1874-1879 (1985)].

The benzodiazepine (BZD) structure class, which has been widelyexploited as therapeutic agents, especially as central nervous system(CNS) drugs, such as anxiolytics, and which exhibits strong binding to"benzodiazepine receptors" in vitro, has not in the past been reportedto bind to CCK or gastrin receptors. Benzodiazepines have been shown toantagonize CCK-induced activation of rat hippocampal neurones but thiseffect is mediated by the benzodiazepine receptor, not the CCK receptor[see J. Bradwejn et al., Nature, 312, 363 (1984)]. Of these reportedBZD's, additionally, the large majority do not contain substituentsattached to the 3-position of the seven membered ring, as it is wellknown in the art that 3-substituents result in decreasing anxioliticactivity, especially as these substituents increase in size. Further, ithas been demonstrated that in the case of the 3-substitutedbenzodiazepines that have been reported, the preferred stereochemistryat position 3 for CNS activity is S, which would correspond to anL-amino acid, such as L-tryptophan.

It was, therefore, an object of this invention to identify substanceswhich more effectively antagonize the function of cholecystokininsand/or gastrin in disease states in mammals, especially in humans. Itwas another object of this invention to prepare novel compounds whichmore selectively inhibit cholecystokinins or inhibit gastrin. It wasstill another object of this invention to develop a method ofantagonizing the functions of cholecystokinin and/or gastrin in diseasestates in mammals. It is also an object of this invention to develop amethod of preventing or treating disorders of the gastrointestinal,central nervous and appetite regulatory systems of mammals, especiallyof humans, or of increasing food intake of animals.

SUMMARY OF THE INVENTION

The present invention is directed to aromatic 1,4-benzodiazepines withfused 5- and 6-membered heterocyclic rings which are antagonists ofcholecystokinins (CCK) and/or gastrin, and are useful in the treatmentand prevention of CCK-related and/or gastrin-related disorders of thegastrointestinal, central nervous and appetite regulatory systems ofmammals, especially of humans, including irritable bowel syndrome,ulcers, excess pancreatic or gastric secretion, acute pancreatitis,motility disorders, neuroleptic disorders, tardive dyskinesia,Parkinson's disease, psychosis, Gilles de la Tourette Syndrome,disorders of the appetite regulatory system, Zollinger-Ellison syndrome,antral G cell hyperplasia, pain (by the potentiation of opioidanalgesics), and malignancies of the lower esophagus, stomach,intestines, and colon. As antagonists of CCK, they may also be used toincrease food intake in animals.

DETAILED DESCRIPTION OF THE INVENTION

The 1,4-benzodiazepines with fused 5- and 6-membered heterocyclic ringsof this invention are those of Formula I: ##STR1## wherein R¹ is H or C₁-C₄ -straight- or branched-chain alkyl;

R² is H, C₁ -C₄ -straight- or branched-chain alkyl, mono- ordisubstituted or unsubstituted phenyl (where the substituent(s) is/areindependently selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, carboxyl, carboxyl-C₁ -C₄ -alkyl,nitro, --CF₃, ##STR2## and hydroxy), 2-, 3- or 4-pyridyl, or --(CH₂)_(m)COOR⁶ ; R³ is ##STR3## R⁴ and R⁵ are independently H, C₁ -C₄ -straight-or branched-chain-alkyl, cyclo-C₃ -C₇ -alkyl, or are connected to form ahetero ring of the form, ##STR4## where k is 2 to 6; R⁶ is H, C₁ -C₄-straight or branched-chain alkyl, cyclo-C₃ -C₇ -alkyl, unsubsititutedor mono- or disubstituted phenyl (where the substituent(s) is/areindependently selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy, nitro, and CF₃), or unsubstituted or mono- ordisubstituted phenyl-C₁ -C₄ -straight or branched-chain alkyl (where thesubstituent(s) is/are independently selected from the group consistingof halo, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, nitro, and CF₃);

R⁷ is α- or β-naphthyl, unsubstituted or mono- or disubstituted phenyl(where the substituent(s) is/are independently selected from the groupconsisting of halo, --NO₂, --OH, --NR⁴ R⁵, C₁ -C₄ -straight- orbranched-chain alkyl, cyano, phenyl, trifluoromethyl, acetylamino,acetyloxy, C₁ -C₄ -straight- or branched-chain alkylthio, SCF₃,C.tbd.CH, CH₂ SCF₃, OCHF₂, S-phenyl, or C₁ -C₄ -straight- orbranched-chain alkoxy), ##STR5## R⁸ is H, C₁ -C₄ -straight- orbranched-chain alkyl, cyclo-C₃ -C₇ -alkyl, --(CH₂)_(n) -- cyclo-C₃ -C₇-alkyl, ##STR6## or branched-chain alkyl, or ##STR7## R¹⁰ is H, --OH, or--CH₃ ; R¹¹ and R¹² are independently C₁ 14 C₄ -straight- orbranched-chain alkyl or cyclo-C₃ -C₇ -alkyl;

R¹⁴ is C₁ -C₄ -straight- or branched-chain alkyl or phenyl-C₁ -C₄-straight- or branched-chain alkyl;

R¹⁸ is H, C₁ -C₄ -straight - or branched-chain alkyl or formyl, acetyl,propionyl or butyryl;

m is 1-to-4;

n is 0-to-4;

q is 0-to-4;

r is 1 or 2;

X¹ is H, --NO₂, CF₃, CN, OH, C₁ -C₄ -straight- or branched-chain alkyl,halo, C₁ -C₄ -straight- or branched-chain alkylthio, C₁ -C₄ -straight-or branched-chain alkoxy, --(CH₂)_(n) COOR⁶, --NR⁴ R⁵, or ##STR8## X²and X³ are independently H, --OH, --NO₂, halo, C₁ -C₄ -straight- orbranched-chain alkylthio, C₁ -C₄ -straight- or branched-chain alkyl, C₁-C₄ -straight- or branched-chain alkoxy, or ##STR9## X⁴ is S, O, CH₂, orNR⁸ ; X⁶ is O or HH;

X⁸ is H or C₁ -C₄ -straight- or branched-chain alkyl;

X⁹ and X_(a) ⁹ are independently NR¹⁸ or O;

Y=CH₂, NR¹, or is absent; and

Z=N or CH₂,

and the pharmaceutically-acceptable salts thereof.

As used herein, the definition of each expression, i.e., m, n, p, C₁ -C₄-alkyl, etc., when it occurs more than once in any structure, isintended to be independent of its definition elsewhere in the samestructure.

In the compounds of Formula I, the preferred stereochemistry forCCK-antagonism relates to D-tryptophan, where C^(4a) and N⁶ of Formula I(C^(3a) and N⁵ for 5-membered heterocycles) correspond to the carbonylcarbon and α-amino nitrogen, respectively, of D-tryptophan and R³occupies the position of the indolylmethyl side chain.

In the compounds of Formula I, the preferred stereochemistry for gastrinantagonism may be either D or L depending on the nature of R³. Forexample, when R³ =(CH₂)_(n) R⁷ or ##STR10## the preferredstereochemistry corresponds to D-tryptophan, as above. When ##STR11##the preferred stereochemistry corrsponds to L-tryptophan.

As used herein, halo is F, Cl, Br, or I; and C₁ -C₄ -alkyl includesmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl.

Preferred compounds according to the present invention include thosewherein R¹ is H or methyl; R² is phenyl or o-F-phenyl; R³ is ##STR12##X¹ is H; X² is H, --NO₂, halo, methyl or methoxy; Y is absent and Z isCH₂ ; or Y is absent and Z is N; or Y is NR¹ and Z is CH₂ ; or Y is CH₂and Z is CH₂ ; or Y is CH₂ and Z is N. For preventing gastrin-relatedproblems preferred compounds include those wherein R³ is ##STR13## andthe stereochemistry corresponds to L-tryptophan. For preventing andtreating CCK-related problems preferred compounds include those whereinR³ is ##STR14## where X² is halo, and wherein R³ is ##STR15## where R⁷is ##STR16## and the sterochemistry corresponds to D-tryptophan.

Even more particularly preferred compounds include, for CCK antagonism:

4(S)-4(2-indolecarbonylamino)-6-phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]-[1,4]-benzodiazepine;

5(S)-5(4-chlorophenylcarbonylamino)-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2-a]-[1,4]-benzodiazepine;

5(S)-5-(2-indolecarbonylamino)-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydro-pyrazino[1,2a]-[1,4]-benzodiazepine;

4(S)2,4-dihydro-4-(2-indolecarbonylamino)-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine;or

5(S)-5-(2-indolecarbonylamino)-7-phenyl-1,2,3,5-tetrahydropyrido[1,2-a]-[1,4]-benzodiazepine;

or for gastrin antagonism:

4(R)-4(3-methoxyphenylaminocarbonylamino)-6-phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]-[1,4]-benzodiazepine;

5(R)-5-(3-methylphenylaminocarbonylamino)-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2,-a]-[1,4]-benzodiazepine;

5(R)-5-(3-chlorophenylaminocarbonylamino)-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydroprazino-[1,2-a]-[1,4]-benzodiazepine;

4(R)-2,4-dihydro-4-(3-methoxyphenylaminocarbonylamino)-6-phenyl-1H-imidazo-[1,2-a]-[1,4]-benzodiazepine;or

5(R)-5-(3-methylphenylaminocarbonylamino)-7-phenyl-1,2,3,5-tetrahydropyrido-[1,2-a]-[1,4]-benzodiazepine.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds of Formula I formed, e.g., from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, isethionic, and the like.

The compounds of Formula I are particularly distinguished frombenzodiazepines of the prior art by the presence of 3-substituents.These Formula I compounds bind strongly to CCK-receptors, but onlyweakly to benzodiazepine-receptors, especially with the increasing sizeof the 3-substituent.

Compounds according to Formula I may be prepared according to Schemes Ithrough VI as follows:

REACTION SCHEME I ##STR17## REACTION SCHEME II ##STR18## REACTION SCHEMEIII ##STR19## REACTION SCHEME IV ##STR20## (where, in the definition ofR³, n is at least 1, when the attachment atom to R⁷ is C; otherwise, nis at least 2) REACTION SCHEME IV (CONT'D) ##STR21## REACTION SCHEME V##STR22## REACTION SCHEME VI ##STR23##

Referring to Reaction Scheme I, a mixture of benzophenone (1), alcohol(2), diisopropylethylamine, and N-methyl-2-pyrrolidine is heated for10-20 hours to give alcohol (3). This alcohol is treated with thionylbromide to provide bromide (4). Heating of (4) with ammonia in ethanolin an autoclave produces the benzodiazepine (5). The nitro group in (5)is selectively reduced with stannic chloride in HCl to an amine which isdeaminated under Sandmeyer conditions yielding (6).

An alternative synthesis of hexahydropiperazinobenzodiazepines is shownin Reaction Scheme II. The 2, 3 piperazindiones (9) are obtained byheating ethyl N-(2,2-diethoxyethyl)-N-methyloxamate (7) withp-substituted aniline (8) and potassium cyanide in acetic acid. A smallamount of the corresponding carboxamide derivative resulting fromhydrolysis of the nitrile is often observed. Reaction of (9a) withalane-triethylamine complex yielded the primary amine (10). Acylation of(10) is accomplished by using the appropriate carboxylic acid chloridesto yield (11), which cyclize smoothly when heated with a mixture ofphosphorus oxychloride and phosphorus pentoxide to yield the desiredhexahydropyrazino[1,2-a][1,4,]benzodiazepines (12).

Referring now to Reaction Scheme III, benzodiazepine (13) is treatedfirst with sodium methoxide and then with carbobenzoxybromoethyl- orpropylamine to give (14). Compound (14) is then treated with a solutionof HBr in glacial acetic acid to give the free amino derivative (15).The cyclodehydration product (16) is formed by heating (15) under refluxin ethanol.

Referring now to Reaction Scheme IV, the anion (18) is generated fromcompounds produced in Schemes I-V by the procedure of J. Org. Chem., 46,3945 (1981) using lithium diisopropylamide (LDA) or using potassiumtert-butoxide.

(18) can be variously treated. For example, the hydroxy alkyl derivative(20) is generated by adding an aldehyde to a solution of (18). Treatmentof (18) with an epoxide yields the hydroxyethyl derivative (19). Bytreating (18) with an alkyl halide, the alkyl derivative (17) isproduced.

An alternative procedure for obtaining (17) is to treat the compoundsfrom Scheme III with an alkyl halide and a strong base such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and heating.

Reaction Scheme V describes the formation of R³ =keto compounds ofFormula I. These are produced by treating the anion (18) with an acidhalide or anhydride. This reaction usually produces both isomers (21)and (22). When the reaction is run in the presence of peroxide, thehydroxy compounds (23) and (24) are produced.

Reaction Scheme VI describes the formation of Formula I compounds whereR³ is a substituted amino moiety. The amino compounds (26) may beobtained by nitrosation of (18) followed by reduction of the oxime (25)with Raney nickel and hydrogen.

When (26) is treated with an alkyl halide, the N-alkyl derivative (28)is produced.

Treatment of (26) with an acid halide or anhydride produces the N-acylderivative (30).

Compound (26) may also be treated with an N-protected α-amino acid and acoupling reagent such as DCC or DPPA (diphenylphosphorylazide) to givethe amides of structure (27).

Treatment of compound (26) with an isocyanate gives the ureas (29).

The pharmaceutically-acceptable salts of the compounds of presentinvention may be synthesized from the compounds of Formula I whichcontain a basic moiety by conventional chemical methods. Generally, thesalts are prepared by reacting the free base with stoichiometric amountsof or with an excess of the desired salt-forming inorganic or organicacid in a suitable solvent or in various combinations of solvents.

Screening of the novel compounds according to the present invention todetermine biological activity and obtain an IC₅₀ value for them, inorder to identify significant CCK-antagonism, may be accomplished usingan ¹²⁵ I-CCK-receptor binding assay and in vitro isolated tissuepreparations. In order to identify significant gastrin antagonism, ¹²⁵I-gastrin and ³ H-pentagastrin binding assays are used. These testsinvolve the following:

CCK Receptor Binding (Pancreas) Method

CCK-8, radiolabeled with ¹²⁵ I-Bolton Hunter reagent (2000 Ci/mmole) ispurchased from New England Nuclear (NEN) and receptor binding isperformed according to Innis and Snyder (Proc. Natl. Acad. Sci., 77,6917-6921, 1980), with minor modifications as described in Chang andLotti (Proc. Natl. Acad. Sci. USA, 83, 4923-4926, 1986).

The whole pancreas of a male Sprague-Dawley rat (200-350 g), which hasbeen sacrificed by decapitation, is dissected free of fat tissue andhomogenized in 20 volumes of ice-cold 50 mm Tris HCl (pH 7.7 at 25° C.)with a Brinkmann Polytron PT-10. The homogenates are centrifuged at48,000 g for 10 minutes, then the resulting pellets are resuspended inTris Buffer, centrifuged as above, and resuspended in 200 volumes ofbinding assay buffer (50 mm Tris HCl, pH 7.7 at 25° C., 5 mmdithiothreitol and 0.1 mm bacitracin).

For the binding assay, 25 μl of buffer (for total binding), or unlabeledCCK-8 sulfate sufficient to give a final concentration of 1 μM of CCK-8(for nonspecific binding), or the compounds according to the instantinvention (for determination of antagonism to ¹²⁵ I-CCK binding) and 25μl of ¹²⁵ I-CCK-8 (30,000-40,000 cpm), are added to 450 μl of themembrane suspensions in duplicate or triplicate test tubes. The reactionmixtures are incubated at 37° C. for 30 minutes and then filtered onglass fiber GF/B filters, which are then rapidly washed with 3×4 ml ofice cold Tris HCl containing 1 mg/ml BSA, and the filters are countedwith a Beckman Gamma 5000. For Scatchard analysis to determine themechanism of inhibition of ¹²⁵ I-CCK binding by the most potentcompounds (Ann. N.Y. Acad. Sci., 51, 660, 1949), ¹²⁵ I-CCK-8 isprogressively diluted with increasing concentrations of CCK-8.

CCK Receptor Binding (Brain) Method

¹²⁵ I-CCK-8 binding is performed similarily to the method described bySaito et al. (J. Neurochem., 37, 483-490, 1981), with modificationsdescribed by Chang and Lotti (Proc. Natl. Acad. Sci. USA, 83 4923-4926,1986).

Male Hartley guinea pigs (300-500 g) are sacrificed by decapitation, andthe brains are removed and placed in ice-cold 50 mm Tris HCl(Trizma-7.4) [pH 7.4 at 25° C.]. The cerebral cortex is dissected andused as a receptor source and each gram of fresh guinea pig brain tissueis homogenized in 10 ml of Tris/Trizma buffer with a Brinkmann polytronPT-10. The homogenates are centrifuged at 42,000 g for 15 minutes, thenthe resulting pellets are resuspended in 200 volumes of binding assaybuffer (10 mM N-2-hydroxy-ethylpiperazine-N'-2-ethenesulfonic acid(HEPES), 5 mM MgCl₂, 1 mMethyleneglycol-bis-(β-aminoethylether)-N,N-tetraacetic acid (EGTA), 0.4%BSA (bovine serum albumin) and 0.25 mg/ml bacitracin, pH 6.5).

The remainder of the binding assay method is as described for thepancreas method, except that the reaction mixtures are incubated at 25°C. for 2 hours before centrifugation.

Isolated Guinea Pig Gall Bladder Method

The two halves of the gall bladders, free of adjacent tissue, of maleHartley guinea pigs (400-600 g), which have been sacrificed bydecapitation, are suspended under 1 g tension along the axis of the bileduct in 15 ml organ bath, containing a Kreb's bicarbonate solution of118 mm NaCl, 4.75 mm KCl, 2.54 mm CaCl₂, 1.19 mm KH₂ PO₄, 1.2 mm MgSO₄,25 mm NaHCO₃ and 11 mm dextrose, which is maintained at 32° C. andbubbled with a mixture of 95% O₂ and 5% CO₂. The tissues are washedevery 10 minutes for one hour to obtain equilibrium prior to thebeginning of the study and the isometric contractions of the strips arerecorded using Statham (60 g: 0.12 mm) strain gauges and aHewlett-Packard 77588 recorder.

CCK-8 is added cumulatively to the baths and EC₅₀ 's are determinedusing regression analysis. After washout (every 10 minutes for onehour), the compound to be tested is added at least 5 minutes before theaddition of CCK-8 and the EC₅₀ of CCK-8 in the presence of compound tobe tested is similarly determined.

A shift to the right of the CCK dose response curve without reduction ofthe maximal centractile response, indicates competitive antagonism ofCCK from this method.

Isolated Longitudinal Muscle of Guinea Pig Ileum

Longitudinal muscle strips with attached nerve plexus are prepared asdescribed in Brit. J. Pharmac. 23:; 356-363, 1964; J. Physiol. 194:13--33, 1969. Male Hartley guinea pigs are decapitated and the ileumremoved (10 cm of the terminal ileum is discarded and the adjacent 20 cmpiece used), with a 10 cm piece of the ileum being stretched on a glasspipette. Using a cotton applicator to stroke tangentially away from themesentery attachment at one end, the longitudinal muscle is separatedfrom the underlying circular muscle and the longitudinal muscle is tiedto a thread and by gently pulling, stripped away from the entire muscle.A piece of approximately 2 cm is suspended in 5 ml organ bath containingKrebs solution and bubbled with 95% O₂ and 5% CO₂ at 37° C. under 0.5 gtension. CCK-8 is added cumulatively to the baths and EC₅₀ values in thepresence and absence of compounds to be tested are determined, asdescribed in the gall bladder protocol above.

Gastrin Receptor Binding In Guinea Pig Gastric Glands

Guinea pig gastric mucosal glands are prepared by the procedure ofBerglingh and Obrink, Acta Physiol. Scand. 96: 150 (1976), with a slightmodification according to Praissman et al. C. J. Receptor Res. 3:(1983). Gastric mucosa from male Hartley guinea pigs (300-500 g bodyweight) are washed thoroughly and minced with fine scissors in standardbuffer consisting of the following: 130 mm NaCl, 12 mm NaHCO₃, 3 mm NaH₂PO₄, 3 mm Na₂ HPO₄, 3 mm K₂ HPO₄, 2 mm MgSO₄, 1 mm CaCl₂, 5 mm glucose,4 mm L-glutamine and 25 mm HERPES at pH 7.4. The minced tissues arewashed and incubated in a 37° C. shaker bath for 40 minutes, with thebuffer containing 0.1% collagenase and 0.1% BSA, and bubbled with 95% O₂and 5% CO₂. The tissues are passed twice through a 5 ml glass syringe toliberate the gastric glands, and then filtered through 200 mesh nylon.The filtered glands are centrifuged at 270 g for 5 minutes and washedtwice by resuspension and centrifugation.

The washed guinea pig gastric glands are resuspended in 25 ml ofstandard buffer containing 0.25 mg/ml of bacitracin. For bindingstudies, 10 μl of buffer (for total binding) or gastrin (1 μM finalconcentration, for nonspecific binding) or test compound and 10 μl of¹²⁵ I-gastrin (NEN, 2200 Ci/mmole, 25 pM final) or ³ H-pentagastrin (NEN22 Ci/mmole, 1 nM final) are added to 220 μl of gastric glands intriplicate tubes which are aerated with 95% O₂ and 5% CO₂ and capped.The reaction mixtures, after incubation at 25° C. for 30 minutes, arefiltered under reduced pressure on glass G/F B filters (Whatman) andimmediately washed with 4×4 ml of standard buffer containing 0.1% BSA.The radioactivity on the filters is measured using a Beckman gamma 5500for ¹²⁵ I-gastrin or liquid scintillation counting for ³ H-pentagastrin.

The ability of the instant 3-substituted 1,4-benzodiazepines with 5- and6-membered heterocylic rings to antagonize CCK and gastrin makes thesecompounds useful as pharmaceutical agents for mammals, especially forhumans, for the treatment and prevention of disorders wherein CCK and/orgastrin may be involved. Examples of such disease states includegastrointestinal disorders, especially such as irritable bowel syndromeor ulcers, excess pancreatic or gastric secretion, acute pancreatitis,motility disorders or gastrointestinal neoplasms; central nervous systemdisorders, caused by CCK interactions with dopamine, such as neurolepticdisorders, tardive dyskinesia, Parkinson's disease, psychosis or Gillesde la Tourette Syndrome; disorders of appetite regulatory systems;Zollinger-Ellison syndrome, antral G cell hyperplasia, or pain (by thepotentiation and prolongation of opiate-mediated analgesia); as well ascertain tumors of the lower esophagus, stomach, intestines and colon.

The compounds of the instant invention or pharmaceutically-acceptablesalts thereof, may be administered to a human subject either alone or,preferably, in combination with pharmaceutically-acceptable carriers ordiluents, optionally with known adjuvants, such as alum, in apharmaceutical composition, according to standard pharmaceuticalpractice. The compounds can be administered orally or parenterally,including intravenous, intramuscular, intraperitoneal, subcutaneous andtopical administration.

For oral use of an antagonist of CCK, according to this invention, theselected compounds may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

When a compound according to the instant invention, or a salt thereof,is used as an antagonist or CCK or gastrin in a human subject, the dailydosage will normally be determined by the prescribing physician with thedosage generally varying according to the age, weight, and response ofthe individual patient, as well as the severity of the patient'ssymptoms. However, in most instances, an effective daily dosage will bein the range of from about 0.05 mg/kg to about 50 mg/kg of body weight,and preferably, of from 0.5 mg/kg to about 20 mg/kg of body weight,administered in single or divided doses. In some cases, however, it maybe necessary to use dosages outside these limits.

In the treatment of irritable bowel syndrome, for instance, 1 to 10mg/kg of a CCK antagonist might be administered orally (p.o.), dividedinto two doses per day (b.i.d.). In treating delayed gastric emptying,the dosage range would probably be the same, although the drug might beadministered either intravenously (I.V.) or orally, with the I.V. doseprobably tending to be slightly lower due to better availability. Acutepancreatitis might be treated preferentially in an I.V. form, whereasspasm and/or reflex esophageal, chronic pancreatitis, past vagatomydiarrhea, or treatment of anorexia or of pain associated with biliarydyskinesia might indicate p.o. form administration.

In the use of a gastrin antagonist as a tumor palliative forgastrointestinal neoplasms with gastrin receptors, as a modulator ofcentral nervous system activity, treatment of Zollinger-Ellisonsyndrome, or in the treatment of peptic ulcer disease, a dosage of 0.1to 10 mg/kg administered one-to-four times daily might be indicated.

Because these compounds antagonize the function of CCK in animals, theymay also be used as feed additives to increase the food intake ofanimals, in amounts of from about 0.05 mg/kg to about 50 mg/kg of bodyweight.

The invention is further defined by reference to the following exampleswhich are intended to be illustrative and not limiting.

EXAMPLE 1 Preparation of2,4-dihydro-6-phenyl-1H-imidazo[1,2-a][1,4]benzodiazepine (16, X¹ =H, R²=Ph, Y is absent)

This compound is prepared according to the method of Earley, et al, J.Med. Chem., 11, 774-777 (1968).

EXAMPLE 2 Preparation of2,4-dihydro-4-oximino-6-phenyl-1H-imidazo[1,2-a]-1,4-benzodiazepine (58,X¹ =H, R² =Ph, Y is absent, Z=N)

To a suspension of potassium tert-butoxide (24.9 g, 222 mmole) in 600 mLof dry tetrahydrofuran is added 200 mL of dry tert-butylalcohol at -20°C. under nitrogen.2,4-Dihydro-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine (25 g) in260 mL of tetrahydrofuran is added to this solution via addition funnelwith the resulting solution being stirred for about 2 hours at -20° C.and treated with 17.4 mL (130 mmole) of isoamyl nitrite. The reactionmixture is warmed to 0° C. over approximately 15 minutes and quenchedwith the addition of 60 mL of cold water and 20 mL of glacial aceticacid and all solvents are removed under reduced pressure. The residue ispartitioned between ethyl acetate (600 mL) and brine (100 mL), with thephases being separated and the organic extracts dried (Na₂ SO₄) andconcentrated. The resulting product is triturated with ether to giveCompound (58).

EXAMPLE 3 Preparation of4(R,S)-amino-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a]-1,4-benzodiazepine(26, X¹ =H, R² =Ph, Y is absent, Z=N, n=Zero)

A solution of 150 mL of methanol containing 5 g2,4-dihydro-4-oximino-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine istreated with a slurry of active Raney-nickel catalyst¹ in ethanol (10g). The resulting suspension is hydrogenated on a Parr apparatus at 60psi and 23° C. for about 30 hours, and the catalyst is removed byfiltration. The filtrate is concentrated to afford the title compound.

EXAMPLE 4 Preparation of4(R,S)-(2(S)-tert-butoxycarbonylamino-3-phenylpropanoylamino)-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine

Crude4(R,S)-amino-2,4-dihydro-6-phenyl-1H-imidazo-[1,2-a]-[1,4]-benzodiazepine(1.37 g), Boc-L-phenyl-alanine (1.37 g, 5.17 mmole),1-hydroxybenzotriazole (0.07 g, 5.17 mmole), and1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.99 g, 5.17mmole) are combined in DMF (30 mL) and stirred at room temperature. ThepH of the reaction mixture is adjusted to 8.5 with triethylamine, andafter 1/2 hour, the DMF is removed in vacuo, and the residue partitionedbetween ethyl acetate and 10% citric acid solution (10 mL). The layersare separated and the organic phase is washed with sodium bicarbonatesolution (NaHCO₃, saturated). The combined organic layers are washedwith brine, dried over Na₂ SO₄, filtered, and evaporated to dryness invacuo to give the title compound as a mixture of diastereomers.

EXAMPLE 5 Preparation of 4(R andS)-(2(S)-amino-3-phenylpropanoylamino)-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine

4(RS)-(2(S)-tert-Butoxycarbonylamino-3-phenylpropanoylamino)-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a]-[2,4]-benzodiazepine(1.8 gm) is dissolved in EtOAc (25 mL), cooled to 0° C., and thesolution saturated with HCl (g) over a 10 minute period. After stirringan additional 10 minutes, the solvent is removed in vacuo. The residueis dissolved in H₂ O, basified with saturated Na₂ CO₃ (aqueous) andextracted with EtOAc (3x). The organic layers are combined, washed wihbrine, dried over Na₂ SO₄, filtered and rotoevaporated in vacuo, withflash chromatography on silica gel separating the 1/1 pair ofdiastereomers into an upper and a lower component. The individualfractions containing the components are concentrated to dryness to givethe separated diastereomers.

EXAMPLE 6 4(R)- and4(S)-Amino-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine

4(S)-(2(S)-Amino-3-phenylpropanoylamino)-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a][1,4]-benzodiazepine(1.15 g) is combined with phenylisothiocyanate (395 mg, 2.93 mmole) inCH₂ Cl₂ (20 mL) and the mixture is concentrated on a steam bath. Theresulting product is twice diluted with CH₂ Cl₂ (20 mL), both timesbeing reconcentrated on the steam bath. The product is evaporated invacuo and treated with TFA (15 mL) and warmed for 18 minutes in an oilbath thermostated at 52°. The TFA is removed in vacuo, and the residueis treated twice with CH₂ Cl₂ and with Et₂ O (being evaporated in vacuoafter each treatment) and the resulting product is chromatographed onsilica gel. The product fractions are evaporated in vacuo, and theresidue is dissolved in CH₂ Cl₂, washed with a small volume of 5% NaOH,dried over Na₂ SO₄, filtered, and evaporated to give the 4-(S) isomer ofthe title structure.

4(R)-(2(S)-amino-3-phenylpropanoylamino)-6-2,4-dihydro-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepineis converted by the same procedure to the 4-(R) enantiomer of the titlecompound.

EXAMPLE 74(S)-2,4-Dihydro-4-(2-indolecarbonylamino)-6-phenyl-1H-imidazo-[1,2-a]-[1,4]-benzodiazepine(30, X¹ =H, R² =Ph, R³ =NHCO-2-indole, Y is absent, Z=N

4(S)-4-Amino-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine (595 mg) isdissolved in CH₂ Cl₂ (15 mL) and treated with 2-indolecarbonyl chloride(403 mg, 2.24 mmole), followed by triethylamine (227 mg, 2.24 mmole).The mixture is stirred at room temperature for approximately 30 minutesand concentrated in vacuo. The residue is chromatographed on silica geland the combined product fractions are evaporated to dryness in vacuo,before Et₂ O (15 mL) is added three times and evaporated in vacuo togive the title compound.

EXAMPLE 84(R)-2,4-Dihydro-4(3-Methoxyphenylaminocarbonylamino)-6-phenyl-1H-imidazo[1,2-a]-[1,4]-benzodiazepine(29, X¹ =H, R² =Ph, ##STR24## Y is absent, Z=N

To a solution of 85 mg of 4(R)-amino-2,4dihydro-6-1H-imidazo-[1,2-a]-1,4-benzodiazepine in 8 ml of drytetrahydrofuran is added 3-methoxyphenylisocyanate (40 μl, 0.315 mmole)at room temperature. Stirring is continued for 8 more hours and thereaction mixture is filtered with the collected product being washedwith hot methanol and dried in vacuo.

EXAMPLE 9 7-Phenyl-1,2,3,5-tetrahydropyrido[1,2-a][1,4]benzodiazepine(16, X¹ =H, R² =phenyl, Y=CH₂)

This compound is prepared according to the method of Example 1 usingcarbobenzoxypropylamine to furnish a fused 6-membered heterocycle ratherthan a 5-membered one.

EXAMPLE 105-Oximino-7-phenyl-1,2,3,5-tetrahydropyrido[1,2-a]-[1,4]-benzodiazepine(25,X¹ =H, R² =Ph, Y=CH₂, Z=N)

This compound is prepared according to the method of Example 2.

EXAMPLE 115-Amino-7-phenyl-1,2,3,5-tetrahydropyrido[1,2-a]-[1,4]-benzodiazepine(26, X¹ =H, R² =Ph, Y=CH₂, Z=N, n=0)

This compound is prepared according to the method of Example 3 andresolved according to the methods of Examples 4 through 6.

EXAMPLE 125(S)-5-(2-Indolecarbonylamino)-7-phenyl-1,2,3,5-tetrahydropyrido-[1,2-a]-[1,4]-benzodiazepine(30, X¹ =H, R² =phenyl, R³ =NHCO-2-indole, Y=CH₂, Z=N)

This compound is prepared according to the method of Example 7.

EXAMPLE 135(R)-5-(3-Methylphenylaminocarbonylamino)-7-phenyl-1,2,3,5-tetrahydropyrido[1,2-a]-[1,4]-benzodiazepine(29, X¹ =H, R² =phenyl, ##STR25## Y=CH₂, Z=N)

This compound is prepared according to the method of Example 8.

EXAMPLE 146-Phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]-[1,4]-benzodiazepine (6,X¹ =H, Y is absent)

This compound is prepared according to the methods of Muller andStrauss, Helv. Chim, Acta, 65, 2118-2132 (1982).

EXAMPLE 154-Oximino-6-phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo-[1,2a]-[1,4]-benzodiazepine(25, X¹ =H, R² =Ph, Y is absent, Z=CH₂)

This compound is prepared according to the method of Example 2 usinglityium diisopropylamide in place of potassium tert-butoxide.

EXAMPLE 164-Amino-6-phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo-[1,2-a]-[1,4]-benzodiazepine(26, X¹ =H, R² =Ph, Y is absent, Z=CH₂, n=0)

This compound is prepared according to the method of Example 3, with the2 diastereomers being separated chromatographically and resolvedaccording to the methods of Examples 4 through 6.

EXAMPLE 174(S)-4-(2-Indolecarbonylamino)-6-phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]-[1,4]-benzodiazepine(30, X¹ =H, R² =Ph, R³ =NHCO-2-indole, Y is absent, Z=CH₂)

This compound (either configuration at position 3a) is preparedaccording to the method of Example 7.

EXAMPLE 184(R)-4-(3-Methoxyphenylaminocarbonylamino)-6-phenyl-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]-[1,4]-benzodiazepine(29, X¹ =H, Y is absent, Z=CH₂, R² =Ph, ##STR26##

This compound (either configuration at position 3a) is preparedaccording to the method of Example 8.

EXAMPLE 197-Phenyl-1,2,3,4,4a,5-hexahydropyrido[1,2-a]-[1,4]benzodiazepine (6, X¹=H, Y=CH₂)

This compound is prepared according to the methods of Muller andStrauss, Helv. Chim, Acta, 65, 2118-2132 (1982).

EXAMPLE 205-Oximino-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2-a][1,4]benzodiazepine(25,X¹ =H, R² =Ph, Y=CH₂, Z=CH₂)

This compound is prepared according to the method of Example 15.

EXAMPLE 215-Amino-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2-a][1,4]benzodiazepine(26, X¹ =H, R² =Ph, Y=CH₂, Z=CH₂, n=0)

This compound is prepared according to the method of Example 3, with thediastereomers being separated chromatographically and resolved accordingto the methods of Examples 4 through 6.

EXAMPLE 225(R)-5-(3-Methylphenylaminocarbonylamino)-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2-a][1,4]benzodiazepine(29, X¹ =H, R² =Ph, ##STR27## Y=CH₂, Z=CH₂)

This compound (either configuration at position 4a) is preparedaccording to the method of Example 8.

EXAMPLE 235-(S)-5-(4-Chlorophenylcarbonylamino)-7-phenyl-1,2,3,4,4a,5-hexahydropyrido[1,2-a][1,4]benzodiazepine(30, X¹ =H, R² =Ph, ##STR28## Y=Z=CH₂)

This compound (either configuration at position 4a) is preparedaccording to the method of Example 7.

EXAMPLE 243-Methyl-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino-[1,2-a][1,4]-benzodiazepine(12, X¹ =H, R² =Ph or 6, X¹ =H, Y=N--CH₃)

This compound is prepared according to the methods of Muller andStrauss, Helv. Chim. Acta, 65, 2118-2132 (1982), or Smith et al., J.Med. Chem, 23, 952-955 (1980).

EXAMPLE 253-Methyl-5-oximino-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino-benzodiazepine(25, X¹ =H, R² =Ph, Y=N--CH₃ Z=CH₂)

This compound is prepared according to the method of Example 15.

EXAMPLE 265-Amino-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine(26, X¹ =H, R² =Ph, Y=N--CH₃, Z=CH₂, n=0)

This compound is prepared according to the method of Example 3 (eitherconfiguration at position 4a) and resolved according to the methods ofExamples 4 through 6.

EXAMPLE 275(S)-5-(2-Indolecarbonylamino)-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]-benzodiazepine(30, X¹ =H, R² =Ph, R³ NHCO-2-indole, Y=N--CH₃, Z=CH₂)

This compound (either configuration at position 4a) is preparedaccording to the method of Example 7.

EXAMPLE 285(R)-5-(3-Chlorophenylaminocarbonylamino)-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]-benzodiazepine(29, X¹ =H, R² =Ph, ##STR29## Y=N--CH₃, Z=CH₂)

This compound (either configuration at position 4a) is preparedaccording to the method of Example 8.

What is claimed is:
 1. A compound of the formula: ##STR30## wherein R¹is H, or C₁ -C₄ -straight- or branched-chain alkyl;R² is H, C₁ -C₄-straight- or branched-chain alkyl, mono- or disubstituted orunsubstituted phenyl, where the substituent(s) is/are independentlyselected from the group consisting of halo, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, C₁ -C₄ -alkylthio, carboxyl, carboxyl-C₁ -C₄ -alkyl, nitro,--CF₃, ##STR31## and hydroxy, 2-, 3-, or 4-pyridyl, or --(CH₂)_(m) COOR⁶; R³ is ##STR32## R⁴ and R⁵ are independently H, C₁ -C₄ -straight- orbranched-chain-alkyl, cyclo-C₃ -C₇ -alkyl, or are connected to nitrogento form a hetero ring of the form ##STR33## where k is 2 to 6; R⁶ is H,C₁ -C₄ -straight or branched-chain alkyl, cyclo-C₃ -C₇ -alkyl,unsubstituted or mono- or disubstituted phenyl, where the substituent(s)is/are independently selected from the group consisting of halo, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, nitro, and CF₃, or unsubstituted or mono- ordisubstituted phenyl-C₁ -C₄ -straight or branched-chain alkyl, where thesubstituent(s) is/are independently selected from the group consistingof halo, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, nitro, and CF₃ ; R⁷ is α- orβ-naphthyl, unsubstituted or mono- or disubstituted phenyl, where thesubstituent(s) is/are independently selected from the group consistingof halo, --NO₂, --OH, --NR⁴ R⁵, ##STR34## as defined above, C₁ -C₄-straight- or branched-chain alkyl, cyano, phenyl, trifluoromethyl,acetylamino, acetyloxy, C₁ -C₄ -straight- or branched-chain alkylthio,SCF₃, C.tbd.CH, CH₂ SCF₃, OCHF₂, S-phenyl, and C₁ -C₄ -straight- orbranched-chain alkoxy, ##STR35## R⁸ is H, C₁ -C₄ -straight- orbranched-chain alkyl, cyclo-C₃ -C₇ -alkyl, --(CH₂)_(n) -cyclo-C₃ -C₇-alkyl, ##STR36## or branched-chain alkyl, or ##STR37## R¹⁰ is H, --OH,or --CH₃ ; R¹¹ and R¹² are independently C₁ -C₄ -straight- orbranched-chain alkyl or cyclo-C₃ -C₇ -alkyl; R¹⁴ is C₁ -C₄ -straight- orbranched-chain alkyl or phenyl-C₁ -C₄ -straight- or branched-chainalkyl; R¹⁸ is H, C₁ -C₄ -straight- or branched-chain alkyl or formyl,acetyl, propionyl or butyryl; m is 1-to-4; n is 0-to-4; q is 0-to-4; ris 1 or 2; X¹ is H, --NO₂, CF₃, CN, OH, C₁ -C₄ -straight- orbranched-chain alkyl, halo, C₁ -C₄ -straight- or branched-chainalkylthio, C₁ -C₄ -straight- or branched-chain alkoxy, --(CH₂)_(n)COOR⁶, --NR⁴ R⁵, or ##STR38## X² and X³ are independently H, --OH,--NO₂, halo, C₁ -C₄ -straight- or branched-chain alkylthio, C₁ -C₄-straight- or branched-chain alkyl, C₁ -C₄ -straight- or branched-chainalkoxy, or ##STR39## X⁴ is S, O, CH₂, or NR⁸ ; X⁶ is O; X₈ is H or C₁-C₄ -straight- or branched-chain alkyl; X⁹ and X_(a) ⁹ are independentlyNR¹⁸ or O; Y=CH₂ or NR¹ ; and Z=N or CH₂,or apharmaceutically-acceptable salt thereof.
 2. A compound according toclaim 1, wherein R¹ is H or C₁ -C₄ -alkyl;R² is unsubstituted of mono-or disubstituted phenyl, where the substituent(s) is/are independentlyselected from the group consisting of halo, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, nitro, and --CF₃ ; R³ is --(CH₂)_(n) R⁷, ##STR40## or ##STR41##R⁷ is α- or β-naphthyl, unsubstituted or mono- or disubstituted phenyl,where the substituent(s) is/are independently selected from the groupconsisting of halo, nitro, C₁ -C₄ -alkyl, trifluoromethyl and C₁ -C₄-alkoxy, ##STR42## R⁸ is H, or C₁ -C₄ -alkyl; n is 0-to-2; q is 0-to-2;r is 1 or 2; X¹ is H, --NO₂, C₁ -C₄ -alkyl, halo, or C₁ -C₄ -alkoxy; X²and X³ are independently H, --NO₂, halo, C₁ -C₄ -alkyl or C₁ -C₄-alkoxy; X⁴ is S, O, CH₂, or NR⁸ ; X⁸ is H or C₁ -C₄ -alkyl; X⁹ andX_(a) ⁹ are independently NH or O;or a pharmaceutically-acceptable saltthereof.
 3. A compound according to claim 1, whereinR¹ is H or methyl;R² is phenyl or o-F-phenyl; R³ is ##STR43## R⁷ is ##STR44## X¹ is H; X²is H, --NO₂, halo, methyl, or methoxy.
 4. A compound according to claim1, whereinR² is phenyl or o-F-phenyl; R³ is ##STR45## R⁷ is ##STR46## X¹is H; X² is H, --NO₂, halo, methyl, or methoxy; Y is CH₂ ; and Z is CH₂.5. A compound according to claim 1, whereinR² is phenyl or o-F-phenyl;R³ is ##STR47## R⁷ is ##STR48## X¹ is H; X² is H, --NO₂, halo, methyl,or methoxy; Y is N-CH₃ ; and Z is N.
 6. A compound according to claim 1,whereinR² is phenyl or o-F-phenyl; R³ is ##STR49## R⁷ is ##STR50## X¹ isH; X² is H, --NO₂, halo, methyl, or methoxy; Y is CH₂ ; and Z is N.
 7. Acompound according to claim 1 whichis:5(S)-5(4-chlorophenylcarbonylamino)-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2-a]-[1,4]-benzodiazepine;5(S)-5-(2-indolecarbonylamino)-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydro-pyrazino[1,2a]-[1,4]-benzodiazepine;or5(S)-5-(2-indolecarbonylamino)-7-phenyl-1,2,3,5-tetrahydropyrido[1,2-a]-[1,4]-benzodiazepine.8. A compound according to claim 1 whichis:5(R)-5-(3-methylphenylaminocarbonylamino)-7-phenyl-1,2,3,4,4a,5-hexahydropyrido-[1,2,-a]-[1,4]-benzodiazepine;5(R)-5-(3-chlorophenylaminocarbonylamino)-3-methyl-7-phenyl-1,2,3,4,4a,5-hexahydroprazino-[1,2-a]-[1,4]-benzodiazepine;or5(R)-5-(3-methylphenylaminocarbonylamino)-7-phenyl-1,2,3,5-tetrahydropyrido-[1,2-a]-[1,4]-benzodiazepine.9. A pharmaceutical composition comprising a therapeutically-effectiveamount for antagonism of the function of cholecystokinins or gastrin inmammals of one or more compounds according to claim 1, orpharmaceutically-acceptable salts thereof, and apharmaceutically-acceptable carrier.
 10. A composition according toclaim 9, further comprising an adjuvant.
 11. A composition according toclaim 9, wherein the therapeutically-effective amount is from about 0.05to about 50 mg/kg of body weight.
 12. A method of preventing in mammalsor treating mammals for cholecystokinin or gastrin related disorders ofthe gastrointestinal, central nervous or appetite regulatory systemswhich comprises administering to those mammals atherapeutically-effective amount of one or more compounds orpharmaceutically-acceptable salts according to claim
 1. 13. A methodaccording to claim 12, wherein a pharmaceutically-acceptable carrier ora pharmaceutically-acceptable carrier and an adjuvant are alsoadministered.
 14. A method according to claim 13, wherein the mammalsare humans and a therapeutically-effective amount is from about 0.1 toabout 20 mg/kg of body weight, administered in single or divided doses.15. A method of increasing food intake in animals which comprisesadministering approximately 0.05 mg/kg to 50 mg/kg of body weight of oneor more compounds or pharmaceutically-acceptable salts according toclaim 1.